Rethinking Assessment of the Human Muscle Metaboreflex: Why the Stimulus Matters

Abstract

In a publication titled “Innovative dose-response assessment of the metaboreflex with indirect control of intramuscular metabolic perturbation in humans” [1], Kouzkouz and colleagues performed elegant experiments that shed light on the methodological assessment of the muscle metaboreflex in humans. They also report intriguing findings regarding sex differences in mean arterial pressure (MAP) responses to metaboreflex activation that challenge existing views.

Alongside feedforward signals from the cerebral cortex (central command), and feedback signals from the arterial and cardiopulmonary baroreflexes and the arterial chemoreflex, feedback from Group III/IV muscle afferents within the exercising muscle (i.e., the exercise pressor reflex) is instrumental for orchestrating the cardiovascular responses to exercise [2]. In humans, the metabolically sensitive component of the exercise pressor reflex (i.e., the muscle metaboreflex) has been studied for almost a century. Already in 1937, Alam and Smirk [3] demonstrated the concept of a chemical/metabolic reflex emerging from skeletal muscle by demonstrating that blood pressure remained elevated above resting levels when contraction-induced metabolites were trapped in the leg by circulatory occlusion of the thigh immediately upon the cessation of dynamic calf exercise in humans. Today, it is well-established, that once activated by the accumulation of metabolites produced by contracting skeletal muscle, the metaboreflex evoke an increase in sympathetic nerve activity (SNA) that, via constriction of the systemic vasculature and modulation of the chronotropic and inotropic functions of the heart, increases arterial blood pressure and supports the redistribution of blood flow during exercise [4]. In addition to the exercising limb muscle metaboreflex, the stimulation of phrenic afferent fibers in response to elevated work of breathing, such as during sustained, high-intensity whole-body exercise, also evokes reflex sympathoexcitation (i.e., the respiratory metaboreflex) with consequences for blood flow distribution to the active limb muscle [5] and potentially, the brain [6].

Post-exercise circulatory occlusion (PECO) is a useful model to activate and isolate the muscle metaboreflex, as it permits investigation of metaboreceptor stimulation independent of influences from mechanoreceptor stimulation and central command. Using such experimental model, Kouzkouz and colleagues performed a dose–response assessment of the muscle metaboreflex in 30 healthy adults (15 females) using four consecutive bouts of sustained submaximal isometric knee-extension exercise of progressively longer duration, followed by 2 min of PECO [1] (Figure 1). The dose–response approach allowed the authors to assess linearity of the responses to graded levels of metaboreflex activation. Metaboreflex activation (i.e., intramuscular metabolic perturbation) was estimated from changes in quadriceps twitch force (ΔQTW). In addition, the authors introduced the concept of metaboreflex gain (ΔMAP/ΔQTW), intended to reflect the sensitivity of the reflex by normalizing the efferent output, evaluated by ΔMAP, to the underlying metabolic perturbation estimated indirectly via ΔQTW.

Notably, the authors found that metaboreflex gain (or sensitivity) varied across exercise bouts, which, importantly, suggests that studies based on a single assessment may yield contrasting conclusions depending on the level of metaboreflex activation. Another interesting aspect in the study was the investigation of potential sex differences in the pressure response to graded levels of metaboreflex activation. Although the literature is somewhat equivocal, several studies have demonstrated attenuated blood pressure responses to metaboreflex activation in young females compared to age-matched males (e.g., [7]), which seems independent of muscle group and whether the workload is absolute or relative, as demonstrated by blunted MAP responses to metaboreflex activation in females that are consistent between limb (i.e., muscle metaboreflex) and respiratory muscle (i.e., respiratory metaboreflex), when evoked at the same absolute and relative workload [8]. Indeed, when Kouzkouz and colleagues assessed the metaboreflex ‘classically’ (i.e., at the same relative workload, but without adjustment to ΔQTW), a greater ΔMAP was observed in males compared to females at two out of four PECO bouts, with no sex differences at the other two bouts. However, when the sensitivity of the metaboreflex was assessed (metaboreflex gain) by indirect control of the extent of intramuscular metabolic perturbation (i.e., ΔQTW), any differences between sexes were abolished.

These novel results stress the importance of considering the metabolic stimuli when assessing the metaboflex and indicate earlier reports on sex differences in the metaboreflex may, in fact, not reflect differences in the functioning or responsiveness of the metaboreflex, but rather result from lower metabolic disturbance in females, even at similar relative workloads. This hypothesis is supported by studies taking biopsies from male and female skeletal muscle showing that females exhibit a greater proportion of oxidative, fatigue-resistant Type I muscle fibers relative to males [9].

Accurate assessment of the muscle metaboreflex has clinical relevance, as evidence from both human and animal studies suggests that several cardiovascular disease states are associated with an overactive metaboreflex, resulting in exaggerated increases in SNA and MAP during metaboreflex activation [10]. Thus, a call for concern has been raised regarding widespread use of the ‘popular’ blood flow restriction exercise, as exaggerated blood pressure responses to this type of exercise in individuals who already have heightened resting SNA and/or MAP (e.g., hypertension) could potentially precipitate adverse and potentially life-threatening cerebrovascular or cardiovascular events [10].

When interpreting the findings by Kouzkouz et al. [1], some methodological considerations warrant attention. For example, the afferent arm of the metaboreflex (i.e., metabolic perturbation) was estimated indirectly via the extent of peripheral muscle fatigue quantified by ΔQTW. Although prior studies report a close relationship between intramuscular metabolite accumulation and impaired muscle force production, Kouzkouz et al. [1] lack direct evidence of metabolite accumulation. Furthermore, they relied on ΔMAP to represent metaboreflex efferent output rather than direct recordings of muscle SNA. Given that blood pressure represents only one of several physiological outputs to metaboreflex activation (all mediated by increased SNA and vagal withdrawal), MAP does not fully reflect the complex integrative nature of the muscle metaboreflex.

The author declares no conflicts of interest.

This article is linked to Kouzkouz et al. papers. To view this article, visit https://doi.org/10.1111/apha.70303.

The author has nothing to report.